2022 EBMT Celebrities Comment on Professor Huang Wenrong: Research Progress of Autologous Hematopoietic Stem Cell Transplantation for Consolidation Treatment of PCNSL

Introduction Primary central nervous system lymphoma (PCNSL) is an extralymphatic non-Hodgkin lymphoma (NHL) that originates in the central nervous system
.

The treatment of PCNSL includes induction therapy and consolidation therapy.
Induction therapy is mostly based on high-dose methotrexate (HD-MTX) combined chemotherapy as the first-line therapy.
There are various consolidation therapy options.
Young patients mostly use high-dose chemotherapy and autologous hematopoietic stem cells.
Transplantation (HDC-ASCT) for consolidation therapy
.

Autologous hematopoietic stem cell transplantation (ASCT) plays an important role in the consolidation therapy of PCNSL
.

Two studies by Lithuanian and Polish researchers on different induction chemotherapy regimens combined with ASCT consolidation in the treatment of PCNSL were selected for poster presentation at the 48th European Society for Blood and Marrow Transplantation (EBMT) annual meeting in 2022.
Yimaitong specially invited PLA General Hospital Professor Huang Wenrong commented on this
.

S.
Cernauskiene et al conducted a retrospective study of patients receiving consolidation therapy with ASCT following induction therapy with HD-MTX, rituximab (Rtx), cytarabine (AraC), and thiotepa (TT) regimens.
The medical records of all newly diagnosed PCNSL patients who underwent ASCT consolidation therapy at Vilnius University Hospital, Lithuania, from 2009 to 2021
.

Study Methods Patients received 4 cycles of induction therapy with Rtx (375mg/m2) and HD-MTX (3.
5-8g/m2), a 10-day cycle; followed by 2 cycles of high-dose AraC (2-3g/m2) q12h), TT (40mg/m2) and Rtx (375mg/m2), 21 days as a cycle
.

MRI was performed after 4 cycles of R-HD-MTX and after 2 cycles of R-HD-AraC-TT
.

Stem cell mobilization and harvesting were performed after the 1st R-HD-AraC-TT cycle
.

ASCT was performed in patients who achieved complete remission (CR), unproven complete remission (CRu), or partial remission (PR)
.

The ASCT conditioning regimen included Rtx on day -7, carmustine 400mg/m2 on day -6 and TT 5mg/kg q12h on days -5 and -4
.

Study endpoints included progression-free survival (PFS), overall survival (OS), and grade 3-5 non-hematologic toxicity (CTCAE v5.
0)
.

RESULTS: Fifty-seven patients were enrolled, and the median age at diagnosis was 55 years (range: 36-75 years)
.

35% of patients were older than 60 years
.

DLBCL was the most common histological type, accounting for 96%
.

Forty-two percent of patients had poor performance status (ECOG ≥ 2), and 59% were classified as intermediate or high risk by the IELSSG score
.

The median time from diagnosis to transplantation was 4 months
.

The median number of hematopoietic stem cells reinfused was 5.
5×106/kg
.

All patients achieved rapid hematopoietic recovery with a median hospital stay of 26 days
.

The most common complication was infection (febrile neutropenia in 26, bacteremia in 9, pneumonia in 3, and urinary tract infection in 2)
.

There were 24 cases of grade 3-4 mucositis and 2 cases of pseudomembranous colitis
.

There was one treatment-related death due to sepsis and fungal pneumonia
.

65% (37/57) of patients achieved CR or CRu before transplantation, and 35% (20/57) of patients achieved PR
.

At +100 days post-transplant, the CR rate increased to 93%
.

After a median follow-up of 64.
5 months, 40/57 (70%) patients were still alive
.

Median OS and PFS were not reached at last follow-up
.

The 2- and 5-year PFS rates were 85% and 71%, respectively, and the 2- and 5-year OS rates were 85% and 72%, respectively
.

Responding patients had a similar prognosis (figure below)
.

Conclusions The 12-year follow-up results suggest that induction chemotherapy with HD-MTX, AraC, TT, and Rtx followed by ASCT consolidation therapy is safe in newly diagnosed PCNSL patients and may lead to better transplant-ready patients.
high survival rate
.

B.
Ostrowska et al evaluated a regimen of rituximab, methotrexate, ifosfamide, vincristine (R-MIV) followed by 1 cycle of cytarabine combined with thiotepa Efficacy and tolerability of HDC-ASCT in the treatment of PCNSL
.

Methods: Sixty immunocompetent adult patients with PCNSL treated at the Marie Curie National Institute of Oncology, Poland, between February 2015 and March 2021 were included in the study
.

Patients were given 6 cycles of rituximab, methotrexate (3.
5g/m2), ifosfamide, and vincristine (R-MIV/every two weeks) and 1 cycle of cytarabine Combined treatment with thiotepa
.

Patients with CR or PR continued to use thiotepa 5mg/kg bid for consolidation therapy on days -5 and -4; carmustine 400mg/m2 was given on days -5; on days -5, -4, -3 Etoposide 150 mg/m2 was given every day, followed by ASCT
.

Whole brain radiotherapy (24-36Gy) for patients not eligible for HDC-ASCT
.

Results Thirty-nine (65%) patients were eligible for HDC-ASCT, of which 30 received HDC-ASCT
.

Two CR patients are currently awaiting HDC-ASCT
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Seven patients did not receive HDC-ASCT due to progression (n=2), patient refusal (n=2), and induction therapy-related toxicity (n=3)
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The median age of the 30 transplant patients was 56 years (range: 19-66 years)
.

According to CT/MRI assessment, after induction therapy, 17 patients were CR, 7 patients were CRu, and 6 patients were PR
.

Peripheral blood stem cell collection was performed after 1 R-MIV cycle and an average of 483.
4 (range: 187-1040.
7) x 106 CD34+ cells were collected, corresponding to 5.
73 (range: 2.
55-11.
64) x 106 cells/kg
.

The average length of hospital stay from the date of stem cell reinfusion was 14 days
.

The mean time to hematologic recovery to PLT>25G/L and NEU>0.
5G/L was 9 days and 8 days, respectively
.

Grade 3-4 neutropenia and thrombocytopenia (CTCAE v5.
0) were observed in all patients (mean duration 6 and 7 days, respectively), with grade ≥3 anemia in 7 patients (mean duration 1 day), 1 patient developed grade 3 transaminase elevation (lasting 2 days)
.

Nephrotoxicity was not observed
.

The most common grade 3-4 toxicities were diarrhea (10 patients, mean 4 days) and mucositis (17 patients, mean 5 days)
.

Febrile neutropenia (average duration 2.
5 days) occurred in 17 patients
.

Blood culture did not reveal any related pathogens except for one case confirmed as Enterobacter cloacae and Klebsiella oxytoca
.

Two patients (6.
6%) died of transplant-related complications (septic shock and neurotoxicity)
.

With a median follow-up of 22 months (range: 2-69 months), 23 transplant patients were in CR, and the 2-year PFS and OS rates after ASCT were 79% (95% CI: 66-92) and 79% ( 95%CI: 66-92)
.

Four patients experienced recurrence at 2, 5, 6, and 42 months after ASCT
.

Conclusion This study shows that HDC-ASCT is a relatively safe and effective treatment method for PCNSL patients after R-MIV induction therapy
.

Professor Huang Wenrong commented that PCNSL is a rare tumor, 95% of which are diffuse large B cells.
The SEER in the United States and the epidemiological survey in Australia both suggest that due to the increase in the elderly population, the incidence of PCNSL has increased from the previous 0.
1/100,000 in recent years.
to 0.
4/100,000 3
.

Consolidation therapy after induction therapy for PCNSL is very important to maintain disease remission or even cure.
The current consolidation therapy options mainly include intensive consolidation, whole-brain radiotherapy and ASCT.
Whole-brain radiotherapy and ASCT are the most effective ones.
The quality of life is significantly better than that of whole brain radiotherapy 4
.

In a retrospective analysis by Prof.
S.
Cernauskiene et al at the 48th EBMT Annual Meeting 1, the remission rate of PCNSL patients was significantly improved after ASCT with carmustine + cetipa pretreatment, and the CR/CRu rate increased from The 65% before transplantation increased to 93% after transplantation, and the 5-year PFS rate was as high as 71%
.

This result is significantly better than traditional MTX-based induction chemotherapy and whole-brain radiotherapy in which the long-term survival is only about 25% 5
.

In addition to focusing on the efficacy of ASCT in the treatment of PCNSL patients, Prof.
Ostrowska from Poland reported on the safety of transplantation 2
.

ASCT is generally safe and effective in the treatment of PCNSL, but 6.
6% of the 30 transplant patients died of transplant-related complications such as septic shock and neurotoxicity, which also suggests that ASCT requires the optimization of the whole process, including epilepsy, etc.
Prevention of neurotoxicity, prevention of infection and bleeding,
etc.

Experienced transplant centers have mature transplant procedures and treatment plans, and new transplant units can communicate with experienced transplant centers to improve related treatment levels
.

In view of the good efficacy of ASCT in controlling disease and improving quality of life, in our clinical practice, in our clinical practice, whether patients with naïve or relapsed/refractory PCNSL, if the patient's body can tolerate ASCT, we will actively recommend ASCT in order to achieve The purpose of eradicating PCNSL
.

At present, there are 3 PCNSL patients in our transplant ward who are undergoing ASCT, and 1 61-year-old elderly PCNSL patient who received carmustine + high-dose cetepa pretreatment has been remodeled and ready to go out of the warehouse, and the transplant process went smoothly without any obvious complications.
The other 2 cases have also completed autologous hematopoietic stem cell reinfusion and are currently recovering
.

For the ASCT conditioning regimen for PCNSL, it is recommended to use a conditioning regimen containing high-dose cetepa, which can further improve the complete remission rate and significantly improve the cure rate through ASCT; the specific conditioning regimen can be based on body tolerance and early chemotherapy.
TBC or TT-BCNU regimens containing cetepa were selected based on the intensity and depth of treatment response
.

With the deepening of our understanding of PCNSL, it is believed that more clinicians will recommend ASCT for PCNSL patients, so that more PCNSL patients can be cured, which will greatly improve the overall survival prognosis of PCNSL patients
.

Professor Huang Wenrong, MD, Chief Physician, Postgraduate Supervisor The project leader of the Standing Committee of the Blood Precision Diagnosis and Treatment Committee of the Chinese Research Hospital Association is responsible for the National Natural Science Foundation of China, the military project, and the capital health development scientific research project
.

The first author or corresponding author of 1 second prize of the Army Science and Technology Progress Award has published 21 clinical SCI papers in international journals such as Oncogene, Bone marrow transplant, Cell Transplantation, Frontier Oncology, Transfusion, Annals of Hematology, Clinical transplant, Leukemia & lymphoma, etc.
More than 50 papers published in domestic journals Reference sources: 1.
S.
Cernauskiene, U.
Ringeleviciute, A.
Zucenka, et al.
OUTCOME OF PATIENTS WITH NEWLY DIAGNOSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA AFTER SEQUENTIAL HIGH-DOSE METHOTREXATE, CYTARABINE, THIOTEPA BASED CHEMOIMMUNOTHERAPY FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION.
The 48th Annual Meeting of the EBMT.
Abstract P599.
2.
B.
Ostrowska, J.
Romejko-Jarosinska, K.
Domanska-Czyz, et al.
AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION FOR PRIMARY CENTRAL NERVOUS LYMPHOMA.
A SINGLE INSTITUTION EXPERIENCE.
The 48th Annual Meeting of the EBMT.
Abstract P609.
3.
Farrall AL, Smith JR.
Changing Incidence and Survival of Primary Central Nervous System Lymphoma in Australia: A 33-Year National Population-Based Study.
Cancers (Basel).
2021 Jan 22;13(3):403.
doi: 10.
3390/cancers13030403.
4.
[1] Cheng Li, Huang Wenrong.
Autologous hematopoietic stem cell transplantation in the treatment of primary central nervous system lymphoma[J].
Clinical Metabolism, 2021, 36(10):4.
5.
Biccler JL, Savage KJ, et al.
Risk of death, relapse or progression, and loss of life expectancy at different progression-free survival milestones in primary central nervous system lymphoma.
Leuk Lymphoma.
2019 Oct;60(10):2516-2523.
doi: 10.
1080/10428194.
2019.
1594219.
Editor: Quinta Reviewer: Prof.
Wenrong Huang Typesetting: Wenting pokes "read the original text", we make progress togetherand loss of life expectancy at different progression-free survival milestones in primary central nervous system lymphoma.
Leuk Lymphoma.
2019 Oct;60(10):2516-2523.
doi: 10.
1080/10428194.
2019.
1594219.
Editor: Quinta Reviewer: Prof.
Wenrong Huang Typesetting: Wenting pokes "read the original text", we make progress togetherand loss of life expectancy at different progression-free survival milestones in primary central nervous system lymphoma.
Leuk Lymphoma.
2019 Oct;60(10):2516-2523.
doi: 10.
1080/10428194.
2019.
1594219.
Editor: Quinta Reviewer: Prof.
Wenrong Huang Typesetting: Wenting pokes "read the original text", we make progress together